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Surgical Oncology

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Surgical oncology is a subspecialty within general surgery accredited by the Accreditation Council for Graduate Medical Education that focuses on the surgical management of breast, head and neck, skin and soft tissue, gastrointestinal, hepatopancreaticobiliary, and colorectal cancers.

The primary aim of this text is to provide brief summaries of key clinical trials most relevant to surgical oncology trainees in each of these areas.

BREAST CANCER

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Surgical management of primary tumor

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NSABP B-04: Randomized trial of radical mastectomy, total mastectomy, vs total mastectomy + XRT

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Breast cancer patients with clinically negative axillary nodes were randomized to radical mastectomy, total mastectomy without axillary dissection but with postoperative irradiation, or total mastectomy plus axillary dissection only if their nodes became positive. There were no significant differences in disease-free survival or overall survival. Additionally, women with clinical positive nodes who underwent total mastectomy did not show a survival benefit from adjuvant radiation.[1]

NSABP B-06: Randomized trial of breast conserving surgery versus mastectomy

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Women with tumors 4cm or smaller were randomized to lumpectomy and axillary lymph node dissection with or without breast radiation (50 Gy) or modified radical mastectomy. There were no significant differences between the groups in disease-free survival or overall survival. However, ipsilateral recurrences were decreased with the addition of breast radiation to lumpectomy compared to lumpectomy alone.[2]

Milan 1

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NSABP B-17

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EORTC 10853

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ECOG E5193

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Surgical management of axilla

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ACOSOG Z0010

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NSABP B-32

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ACOSOG Z0011

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IBCSG 23-01

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ACOSOG 1071

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Adjuvant chemotherapy

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Adjuvant hormonal therapy

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Neoadjuvant chemotherapy

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Oncoplastic surgery

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  • N Bertozzi et al. Oncoplastic breast surgery: comprehensive review. Eur Rev Med Pharmacol Sci. 2017 Jun;21(11):2572-2585. (PMID: 28678328)
  • A Gilmour et al. Oncoplastic breast surgery: A guide to good practice. Eur J Surg Oncol. 2021 Sep;47(9):2272-2285. (PMID: 34001384)

THYROID CANCER

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  • Krzysztof Kaliszewski et al. Thyroid cancer surgery - in what direction are we going? A mini-review. J Int Med Res. 2020 Apr;48(4):300060520914803. (PMID: 32249645)
  • Glenda G Callender et al. Surgery for thyroid cancer. Endocrinol Metab Clin North Am. 2014 Jun;43(2):443-58. (PMID: 24891171)
  • Rataphol Chris Dhepnorrarat et al. New technologies in thyroid cancer surgery. Oral Oncol. 2013 Jul;49(7):659-64. (PMID: 23578371)
  • Leonardo Rossi et al. Recent Trends in Surgical Approach to Thyroid Cancer. Front Endocrinol (Lausanne). 2021 Jun 2;12:699805. (PMID: 34149628)

MELANOMA

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  • Sabrina N Pavri et al. Malignant Melanoma: Beyond the Basics. Plast Reconstr Surg. 2016 Aug;138(2):330e-340e. (PMID: 27465194)
  • Siavash Raigani et al. The Role of Surgery for Melanoma in an Era of Effective Systemic Therapy. (PMID: 28251494)
  • Sarem Rashid et al. Melanoma classification and management in the era of molecular medicine. (PMID: 36410983)

SARCOMA

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Neoadjuvant chemotherapy, chemoradiation, or radiation

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RTOG 9513

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Patients with high-grade sarcoma ≥8 cm received neoadjuvant MAID chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine) and radiation, plus postoperative MAID. Toxicity was significant, but survival was better than anticipated.[3]

Adjuvant chemotherapy[3]

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Sarcoma Meta-Analysis Collaboration

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Data from 14 trials showed increased times to local and distant recurrence and higher recurrence free survival with doxorubicin-based chemotherapy in patients with localized, resectable extremity sarcomas. There was a nonsignificant trend towards increased overall survival.[4]

Italian Randomized Cooperative Trial: Adjuvant chemotherapy vs. observation

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Patients with high-grade or recurrent extremity sarcoma were randomized to receive adjuvant chemotherapy with epirubicin + ifosfamide vs. observation alone. Chemotherapy was associated with significant improvements in disease free survival and there was a nonsignificant trend towards improved 5-year overall survival.[5]

EORTC 62931

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Patients with resected sarcomas were randomized to receive adjuvant chemotherapy with ifosfamide + doxorubicin + lenograstim vs. observation alone. There were no benefits in relapse-free survival or overall survival.[6]

ESOPHAGEAL CANCER

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  • Hiroyuki Kato et al. Treatments for esophageal cancer: a review. Gen Thorac Cardiovasc Surg. 2013 Jun;61(6):330-5. (PMID: 23568356)
  • F G Uzunoglu et al. Surgery of esophageal cancer. Langenbecks Arch Surg. 2013 Feb;398(2):189-93. (PMID: 23354360)

GASTRIC CANCER

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Perioperative chemotherapy

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Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial: Perioperative ECF vs surgery alone

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Patients with resectable adenocarcinoma of stomach, GE junction, or lower esophagus were randomized to perioperative chemotherapy (3 cycles ECF pre-op, 3 cycles ECF post-op) + surgery vs. surgery alone. There were no differences in perioperative morbidity and mortality. Tumors were smaller and less advanced with perioperative chemotherapy. The perioperative chemotherapy group had significantly improved progression free survival and overall survival.[7]

Adjuvant chemoradiation

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Macdonald trial: Perioperative chemoradiation vs surgery alone

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Patients with resected adenocarcinoma of the stomach or GE junction were randomized to surgery + postoperative chemoradiation (5-FU + leucovorin + 45 Gy) vs. surgery alone. The postoperative chemoradiation group had significant longer overall survival and lower relapse rates. Of note, most patients had D0/D1 lymphadenectomy.[8]

Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial: Adjuvant chemotherapy vs. adjuvant chemoradiation

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Patients with resected gastric cancers with D2 lymph node dissection were randomized to postoperative treatment with capecitabine plus cisplatin versus cisplastin plus radiotherapy with capecitabine. Adding radiation to chemotherapy did not significantly lower recurrence rates.[9]

GASTROINTESTINAL STROMAL TUMORS

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Neoadjuvant + adjuvant targeted therapy

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RTOG 0132: Phase II study of neoadjuvant/adjuvant imatinib

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First study that evaluated neoadjuvant + adjuvant imatinib for resectable GIST prospectively. Demonstrated acceptable survival as well as high rates of disease progression after discontinuation of maintenance therapy.[10]

EORTC STBSG pooled analysis

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Pooled data from 10 sarcoma centers. Patients with locally advanced, nonmetastatic GISTs who were treated upfront with neoadjuvant imatinib went on to have an 83% rate of R0 resections. About half of the patients also had adjuvant imatinib.[11]

Adjuvant targeted therapy

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ACOSOG Z9000: Phase II study of adjuvant imatinib

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106 patients who had complete resections but at high risk for recurrence were given imatinib 400 mg daily x 1 year and followed with serial radiologic evaluation. The 5-year OS rate was 83% compared to historical 5-year OS rate of 35%. Recurrence free survival was lower with large tumor size, small bowel primary, KIT exon 9 mutation, high mitotic rate, and older age.[12]

ACOSOG Z9001: Phase III trial of adjuvant imatinib

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Patients who had complete resections of cKIT+ GIST ≥ 3 cm were randomized to imatinib 400 mg or to placebo daily x 1 year after surgical resection. Imatinib significantly improved recurrence-free survival compared with placebo and was well tolerated.[13]

Scandinavian Sarcoma Group SSGXVIII/AIO trial: 1 vs 3 years of adjuvant imatinib

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Patients with resected cKIT+ GIST with high risk of recurrence were randomized to imatinib, 400 mg daily, x 12 months vs. 36 months. Those in the 36 month group had significantly longer 5-year RFS (65.6% vs 47.9%) and longer 5-year overall survival (92.0% vs 81.7%).[14]

Targeted therapy for advanced disease

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B2222 study: Safety of imatinib in advanced GIST

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Imatinib associated with disease control in patients with advanced GIST. Low tumor burden was associated with improved overall survival.[15]

EORTC 62005

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Randomized patients with metastatic or unresectable GIST to 400mg daily vs. 800mg daily. Overall survival was equivalent but there were more side effects with the higher dose. However, progression free survival was longer in patients on higher dose.[16]

S0033/CALGB 150105

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Similar to EORTC 62005. Randomized patients with metastatic or unresectable GIST to 400mg daily vs. 800mg daily. Overall survival was equivalent but there were more side effects with the higher dose. However, no difference in progression free survival was seen.[17]

PANCREATIC ADENOCARCINOMA

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  • Monish Karunakaran, et al. Surgery for pancreatic cancer: current controversies and challenges. Future Oncol. 2021 Dec;17(36):5135-5162. (PMID: 34747183)
  • Hordur Mar Kolbeinsson et al. Pancreatic Cancer: A Review of Current Treatment and Novel Therapies. J Invest Surg. 2023 Dec 31;36(1):2129884. (PMID: 36191926)

HEPATOCELLCULAR CARCINOMA

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Targeted therapy for advanced disease

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SHARP Investigators / Llovet et al: Sorafenib for advanced disease

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Patients with advanced HCC randomized to receive either sorafenib or placebo. Median overall survival was significantly longer in the sorafenib group.[18]

Liver transplantation

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  • Fulya Gunsar et al. Liver Transplantation for Hepatocellular Carcinoma Beyond the Milan Criteria. Exp Clin Transplant. 2017 Mar;15(Suppl 2):59-64. (PMID: 28302001)
  • Gonzalo Sapisochin et al. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017 Apr;14(4):203-217. (PMID: 28053342)

COLORECTAL CANCER

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  • Lynda Wyld et al. The evolution of cancer surgery and future perspectives. Nat Rev Clin Oncol. 2015 Feb;12(2):115-24. (PMID: 25384943)
  • Ioannis G Papanikolaou et al. Robotic surgery for colorectal cancer: systematic review of the literature. Surg Laparosc Endosc Percutan Tech. 2014 Dec;24(6):478-83. (PMID: 25054567)
  • F E Eckhauser et al. Surgery for primary and metastatic colorectal cancer. Gastroenterol Clin North Am. 1997 Mar;26(1):103-28. (PMID: 9119436)
  • Juan Manuel Sánchez-Hidalgo et al. Colorectal peritoneal metastases: Optimal management review. World J Gastroenterol. 2019 Jul 21;25(27):3484-3502. (PMID: 31367152)

PROSTATE CANCER

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  • Mary Nguyen-Nielsen et al. Diagnostic and Therapeutic Strategies for Prostate Cancer. Semin Nucl Med. 2016 Nov;46(6):484-490. (PMID: 27825428)
  • Anthony J Costello et al. Considering the role of radical prostatectomy in 21st century prostate cancer care. Nat Rev Urol. 2020 Mar;17(3):177-188. (PMID: 32086498)

Prostate brachytherapy

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  • Sunil W Dutta et al. Prostate cancer high dose-rate brachytherapy: review of evidence and current perspectives. Expert Rev Med Devices. 2018 Jan;15(1):71-79. (PMID: 29251165)
  • Samir Abdallah Hanna et al. Brachytherapy guideline in prostate cancer (high and low dose rate). Rev Assoc Med Bras (1992). 2017 Apr;63(4):293-298. (PMID: 28614527)

SKIN CANCER

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  • Nicholas Golda et al. Mohs Micrographic Surgery. Dermatol Clin. 2023 Jan;41(1):39-47. (PMID: 36410982)
  • R K Roenigk et al. Current surgical management of skin cancer in dermatology. J Dermatol Surg Oncol. 1990 Feb;16(2):136-51. (PMID: 2406310)
  • Michael G Brandt et al. Nonmelanoma Skin Cancer. Facial Plast Surg Clin North Am. 2019 Feb;27(1):1-13. (PMID: 30420063)
  • H D Vuyk et al. Mohs micrographic surgery for facial skin cancer. Clin Otolaryngol Allied Sci. 2001 Aug;26(4):265-73. (PMID: 11559334)

ROBOTIC SURGERY

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  • Matthew Gettman et al. Innovations in robotic surgery. Curr Opin Urol. 2016 May;26(3):271-6. (PMID: 26716566)
  • Andrew Brodie et al. The future of robotic surgery. Ann R Coll Surg Engl. 2018 Sep;100(Suppl 7):4-13. (PMID: 30179048)

RADIOSURGERY

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  • Daniel M Trifiletti et al. The evolution of stereotactic radiosurgery in neurosurgical practice. J Neurooncol. 2021 Feb;151(3):451-459. (PMID: 33611711)
  • Antonio A F De Salles et al. Intracranial stereotactic radiosurgery: concepts and techniques. Neurosurg Clin N Am. 2013 Oct;24(4):491-8. (PMID: 24093567)
  • Ajay Niranjan et al. Radiobiology, principle and technique of radiosurgery. Prog Neurol Surg. 2008;21:32-42. (PMID: 18810197)
  • Manjul Tripathi et al. Radiosurgery for Neurosurgeons. Neurol India. 2023 Mar-Apr;71(12 Suppl 2):S230-S232. (PMID: 37026357)

References

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  1. ↑ Fisher, Bernard; Jeong, Jong-Hyeon; Anderson, Stewart; Bryant, John; Fisher, Edwin R.; Wolmark, Norman (2002). "Twenty-Five-Year Follow-up of a Randomized Trial Comparing Radical Mastectomy, Total Mastectomy, and Total Mastectomy Followed by Irradiation". New England Journal of Medicine. 347 (8): 567–75. doi:10.1056/NEJMoa020128. PMID 12192016.
  2. ↑ Fisher, Bernard; Anderson, Stewart; Bryant, John; Margolese, Richard G.; Deutsch, Melvin; Fisher, Edwin R.; Jeong, Jong-Hyeon; Wolmark, Norman (2002). "Twenty-Year Follow-up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of Invasive Breast Cancer". New England Journal of Medicine. 347 (16): 1233–41. doi:10.1056/NEJMoa022152. PMID 12393820.
  3. ↑ a b Kraybill, William G.; Harris, Jonathan; Spiro, Ira J.; Ettinger, David S.; Delaney, Thomas F.; Blum, Ronald H.; Lucas, David R.; Harmon, David C.; Letson, G. Douglas; Eisenberg, Burton (2010). "Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall". Cancer. 116 (19): 4613–21. doi:10.1002/cncr.25350. PMC 3780573. PMID 20572040.
  4. ↑ "Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data". The Lancet. 350 (9092): 1647–54. 1997. doi:10.1016/S0140-6736(97)08165-8. PMID 9400508.
  5. ↑ Frustaci, Sergio; Gherlinzoni, Franco; De Paoli, Antonino; Bonetti, Marco; Azzarelli, Alberto; Comandone, Alessandro; Olmi, Patrizia; Buonadonna, Angela; Pignatti, Giovanni; Barbieri, Enza; Apice, Gaetano; Zmerly, Hassan; Serraino, Diego; Picci, Piero (2001). "Adjuvant Chemotherapy for Adult Soft Tissue Sarcomas of the Extremities and Girdles: Results of the Italian Randomized Cooperative Trial". Journal of Clinical Oncology. 19 (5): 1238–47. doi:10.1200/JCO.2001.19.5.1238. PMID 11230464.
  6. ↑ Woll, Penella J; Reichardt, Peter; Le Cesne, Axel; Bonvalot, Sylvie; Azzarelli, Alberto; Hoekstra, Harald J; Leahy, Michael; Van Coevorden, Frits; Verweij, Jaap; Hogendoorn, Pancras CW; Ouali, Monia; Marreaud, Sandrine; Bramwell, Vivien HC; Hohenberger, Peter (2012). "Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): A multicentre randomised controlled trial". The Lancet Oncology. 13 (10): 1045–54. doi:10.1016/S1470-2045(12)70346-7. PMID 22954508.
  7. ↑ Cunningham, David; Allum, William H.; Stenning, Sally P.; Thompson, Jeremy N.; Van De Velde, Cornelis J.H.; Nicolson, Marianne; Scarffe, J. Howard; Lofts, Fiona J.; Falk, Stephen J.; Iveson, Timothy J.; Smith, David B.; Langley, Ruth E.; Verma, Monica; Weeden, Simon; Chua, Yu Jo; Magic Trial, Participants (2006). "Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer". New England Journal of Medicine. 355 (1): 11–20. doi:10.1056/NEJMoa055531. PMID 16822992.
  8. ↑ MacDonald, John S.; Smalley, Stephen R.; Benedetti, Jacqueline; Hundahl, Scott A.; Estes, Norman C.; Stemmermann, Grant N.; Haller, Daniel G.; Ajani, Jaffer A.; Gunderson, Leonard L.; Jessup, J. Milburn; Martenson, James A. (2001). "Chemoradiotherapy after Surgery Compared with Surgery Alone for Adenocarcinoma of the Stomach or Gastroesophageal Junction". New England Journal of Medicine. 345 (10): 725–30. doi:10.1056/NEJMoa010187. PMID 11547741.
  9. ↑ Lee, Jeeyun; Lim, Do Hoon; Kim, Sung; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Choi, Min Gew; Sohn, Tae Sung; Noh, Jae Hyung; Bae, Jae Moon; Ahn, Yong Chan; Sohn, Insuk; Jung, Sin Ho; Park, Cheol Keun; Kim, Kyoung-Mee; Kang, Won Ki (2012). "Phase III Trial Comparing Capecitabine Plus Cisplatin Versus Capecitabine Plus Cisplatin with Concurrent Capecitabine Radiotherapy in Completely Resected Gastric Cancer with D2 Lymph Node Dissection: The ARTIST Trial". Journal of Clinical Oncology. 30 (3): 268–73. doi:10.1200/JCO.2011.39.1953. PMID 22184384.
  10. ↑ Wang, Dian; Zhang, Qiang; Blanke, Charles D.; Demetri, George D.; Heinrich, Michael C.; Watson, James C.; Hoffman, John P.; Okuno, Scott; Kane, John M.; von Mehren, Margaret; Eisenberg, Burton L. (2011). "Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132". Annals of Surgical Oncology. 19 (4): 1074–80. doi:10.1245/s10434-011-2190-5. PMC 3800166. PMID 22203182.
  11. ↑ Rutkowski, Piotr; Gronchi, Alessandro; Hohenberger, Peter; Bonvalot, Sylvie; Schöffski, Patrick; Bauer, Sebastian; Fumagalli, Elena; Nyckowski, Pawel; Nguyen, Buu-Phuc; Kerst, Jan Martijn; Fiore, Marco; Bylina, Elzbieta; Hoiczyk, Mathias; Cats, Annemieke; Casali, Paolo G.; Le Cesne, Axel; Treckmann, Jürgen; Stoeckle, Eberhard; De Wilt, Johannes. H. W.; Sleijfer, Stefan; Tielen, Ronald; Van Der Graaf, Winette; Verhoef, Cornelis; Van Coevorden, Frits (2013). "Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GIST): The EORTC STBSG Experience". Annals of Surgical Oncology. 20 (9): 2937–43. doi:10.1245/s10434-013-3013-7. PMID 23760587.
  12. ↑ Dematteo, Ronald P.; Ballman, Karla V.; Antonescu, Cristina R.; Corless, Christopher; Kolesnikova, Violetta; von Mehren, Margaret; McCarter, Martin D.; Norton, Jeffrey; Maki, Robert G.; Pisters, Peter W. T.; Demetri, George D.; Brennan, Murray F.; Owzar, Kouros (2013). "Long-term Results of Adjuvant Imatinib Mesylate in Localized, High-Risk, Primary Gastrointestinal Stromal Tumor". Annals of Surgery. 258 (3): 422–9. doi:10.1097/SLA.0b013e3182a15eb7. PMC 4041735. PMID 23860199.
  13. ↑ Dematteo, Ronald P; Ballman, Karla V; Antonescu, Cristina R; Maki, Robert G; Pisters, Peter WT; Demetri, George D; Blackstein, Martin E; Blanke, Charles D; von Mehren, Margaret; Brennan, Murray F; Patel, Shreyaskumar; McCarter, Martin D; Polikoff, Jonathan A; Tan, Benjamin R; Owzar, Kouros (2009). "Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial". The Lancet. 373 (9669): 1097–104. doi:10.1016/S0140-6736(09)60500-6. PMC 2915459. PMID 19303137.
  14. ↑ Joensuu, Heikki; Eriksson, Mikael; Sundby Hall, Kirsten; Hartmann, Jörg T.; Pink, Daniel; Schütte, Jochen; Ramadori, Giuliano; Hohenberger, Peter; Duyster, Justus; Al-Batran, Salah-Eddin; Schlemmer, Marcus; Bauer, Sebastian; Wardelmann, Eva; Sarlomo-Rikala, Maarit; Nilsson, Bengt; Sihto, Harri; Monge, Odd R.; Bono, Petri; Kallio, Raija; Vehtari, Aki; Leinonen, Mika; Alvegård, Thor; Reichardt, Peter (2012). "One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor". JAMA. 307 (12): 1265–72. doi:10.1001/jama.2012.347. PMID 22453568.
  15. ↑ Demetri, George D.; von Mehren, Margaret; Blanke, Charles D.; Van Den Abbeele, Annick D.; Eisenberg, Burton; Roberts, Peter J.; Heinrich, Michael C.; Tuveson, David A.; Singer, Samuel; Janicek, Milos; Fletcher, Jonathan A.; Silverman, Stuart G.; Silberman, Sandra L.; Capdeville, Renaud; Kiese, Beate; Peng, Bin; Dimitrijevic, Sasa; Druker, Brian J.; Corless, Christopher; Fletcher, Christopher D.M.; Joensuu, Heikki (2002). "Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors". New England Journal of Medicine. 347 (7): 472–80. doi:10.1056/NEJMoa020461. PMID 12181401.
  16. ↑ Verweij, Jaap; Casali, Paolo G; Zalcberg, John; Lecesne, Axel; Reichardt, Peter; Blay, Jean-Yves; Issels, Rolf; Van Oosterom, Allan; Hogendoorn, Pancras CW; Van Glabbeke, Martine; Bertulli, Rossella; Judson, Ian (2004). "Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial". The Lancet. 364 (9440): 1127–34. doi:10.1016/S0140-6736(04)17098-0. PMID 15451219.
  17. ↑ Blanke, Charles D.; Rankin, Cathryn; Demetri, George D.; Ryan, Christopher W.; von Mehren, Margaret; Benjamin, Robert S.; Raymond, A. Kevin; Bramwell, Vivien H.C.; Baker, Laurence H.; Maki, Robert G.; Tanaka, Michael; Hecht, J. Randolph; Heinrich, Michael C.; Fletcher, Christopher D.M.; Crowley, John J.; Borden, Ernest C. (2008). "Phase III Randomized, Intergroup Trial Assessing Imatinib Mesylate at Two Dose Levels in Patients with Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing the Kit Receptor Tyrosine Kinase: S0033". Journal of Clinical Oncology. 26 (4): 626–32. doi:10.1200/JCO.2007.13.4452. PMID 18235122.
  18. ↑ Llovet, Josep M.; Ricci, Sergio; Mazzaferro, Vincenzo; Hilgard, Philip; Gane, Edward; Blanc, Jean-Frédéric; De Oliveira, Andre Cosme; Santoro, Armando; Raoul, Jean-Luc; Forner, Alejandro; Schwartz, Myron; Porta, Camillo; Zeuzem, Stefan; Bolondi, Luigi; Greten, Tim F.; Galle, Peter R.; Seitz, Jean-François; Borbath, Ivan; Häussinger, Dieter; Giannaris, Tom; Shan, Minghua; Moscovici, Marius; Voliotis, Dimitris; Bruix, Jordi (2008). "Sorafenib in Advanced Hepatocellular Carcinoma". New England Journal of Medicine. 359 (4): 378–90. doi:10.1056/NEJMoa0708857. PMID 18650514.
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